PROJECT SUMMARY/ABSTRACT Previous studies including our own have demonstrated that levels of blood pressure (BP) track from childhood into adulthood. Early life stress such as low parental socioeconomic status (SES) and adverse childhood events (ACEs) is associated with hypertension in adulthood by hastening the trajectory of disease progression. In our well-recognized longitudinal Georgia Stress and Heart (GSH) study, we have recently found a significant association between the number of ACEs and BP trajectories from childhood to young adulthood. Early life stress can lead to a state of heightened systemic inflammation, which persists in adulthood. Stress-induced inflammation is one of the first responses of the immune system to danger. Damage associated molecular patterns (DAMPs) are released by stressed cells to signal danger, and circulating DAMPs are free to activate pattern recognition receptors, subsequently promoting and exacerbating inflammatory cascade in the periphery. However, critical knowledge gaps remain regarding whether these circulating danger molecules are involved in the psychopathological process. Studies have established a key role for low-grade systemic inflammation in the early stage of hypertension and cardiovascular disease (CVD). In spontaneously hypertensive rats, we have recently found that circulating DAMPs may lead to inflammatory activation and cause elevated arterial pressure and vascular dysfunction, and blocking DAMPs may attenuate BP increase. Thus, we propose translating our research in animal models to humans by testing our central hypothesis that is early life stress increases circulating DAMPs, and circulating DAMPs contribute to BP elevation. In this proposal, we will take advantage of our existing longitudinal GSH cohort in which 740 children (50% female and 47% African Americans) have been followed- up 17 times in 27 years (1989-2016). The longitudinal study provides multiple repeated measures of early life stress, BP and CVD risk factors as well as bio-sample collection from childhood to adulthood. DAMPs are endogenous signals that alert the body about danger, and stimulate an inflammatory response in response to environmental stressors. The objective of this cost-effective project undertaking longitudinal approaches using our unique GSH cohort is to establish the relationship of DAMPs with early life stress, and identify the contribution of DAMPs to the trajectories of BP elevation and preclinical CVD. By translating our findings in the animal models to humans, successful completion of our aims will provide both novel molecular mechanisms and biomarkers for early life stress and high BP. Deciphering new paradigms for stress and stress-related hypertension and CVD may inform new preventative strategies, and offer targeted stress management as well as new therapeutic interventions (e.g. HMGB1 blocking therapies).